Multiple drug therapy is a treatment and/or prevention method that may have advantages. For example, it may be used when a single therapeutic agent does not sufficiently elicit a desired biological response or when a single therapeutic agent causes a condition that requires additional treatment. Many times, two or more therapeutic agents are prescribed in tandem for the treatment or maintenance of the same physiological condition, where each therapeutic agent elicits a different or cumulative physiological response. However, multiple drug therapies are also used for the treatment or maintenance of different, yet associated, physiological conditions. For instance, a first therapeutic agent may cause a side effect which in turn requires the use of a second therapeutic agent.
Although multiple drug therapies can be beneficial treatment methods, many times they are a last-resort therapy that becomes burdensome to a patient, both in terms of lifestyle issues, such as the cost associated with taking multiple drugs, and in terms of overall patient health.
Multiple drug therapies often require a patient to take increased levels of each individual therapeutic agent to obtain the desired physiological response. The increased dosing levels in turn lead to greater physiological stress and to an increase in the risks associated with adverse side effects of each individual drug. Although therapeutic agents in multiple drug therapies are commonly intended to elicit complementary physiological responses, drug/drug interactions may be important considerations, especially at high dosing levels. Drug/drug interactions can cause serious and even detrimental side effects for a patient. For instance, competitive binding of two different drugs to the same metabolic enzymes or plasma proteins may cause a disproportionate increase in a single unbound drug substance, leading to adverse side affects and a disruption of the intended therapy.
Some of the disadvantages associated with multiple drug therapies may be overcome by incorporating the multiple pharmacophores involved in a multiple drug therapy into a single therapeutic agent. Rather than the adverse effects known to accompany high dosing levels of different therapeutic agents, the multiple pharmacophores contained within a single compound would likely have beneficial effects. For instance, synergistic effects of the multiple pharmacophores could lead to a decrease in compound dosing levels. Decreased dosing levels in turn can lead to a decrease in drug/drug interactions, a decrease in the risks associated with adverse side effects and a decrease in overall physiological stress. In addition, ease of patient care is provided, as two therapeutic agents may be simply provided in a single formulation.
Physiological conditions associated with arrhythmia often require a patient to take more than one therapeutic agent. The treatment, maintenance or prevention of conditions associated with arrhythmia could benefit from substances that combine the pharmacophore of two or more therapeutic agents into a single compound.
Cardiac ion channels are proteins that reside in the cell membrane and control the electrical activity of cardiac tissue. In response to external stimuli, such as changes in potential across the cell membrane, ion channels can form a pore through the cell membrane, and allow movement of specific ions into or out of the cell. The integrated behavior of thousands of ion channels in a single cell results in an ion current, and the integrated behavior of many ion currents makes up the characteristic cardiac action potential.
Arrhythmia is a variation from the normal rhythm of the heart beat and generally represents the end product of abnormal ion-channel structure, number or function. Both atrial arrhythmias and ventricular arrhythmias are known. The major cause of fatalities resulting from cardiac arrhythmias is the subtype of ventricular arrhythmias known as ventricular fibrillation (VF). Conservative estimates indicate that, in the U.S. alone, each year over one million Americans will have a new or recurrent coronary attack (defined as myocardial infarction or fatal coronary heart disease). About 650,000 of these cases will be first heart attacks and about 450,000 of these cases will be recurrent attacks. About one-third of the individuals experiencing these attacks will die as a result. At least 250,000 individuals a year die of coronary heart disease within 1 hour of the onset of symptoms and before they reach adequate medical aid. These are sudden deaths caused by cardiac arrest, usually resulting from ventricular fibrillation.
Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice and is a cause of morbidity in many individuals (Pritchett E. L., N. Engl. J. Med. 327(14):1031 Oct. 1, 1992, discussion 1031-2; Kannel and Wolf, Am. Heart J. 123(1):264-7 Jan. 1992). The prevalence of AF is likely to increase as the population ages and it is estimated that 3-5% of patients over the age of 60 years have AF (Kannel W. B., Abbot R. D., Savage D. D., McNamara P. M., N. Engl. J. Med. 306(17):1018-22, 1982; Wolf P. A., Abbot R. D., Kannel W. B. Stroke 22(8):983-8, 1991). While AF is rarely fatal, it can impair cardiac function and is a major cause of stroke (Hinton R. C., Kistler J. P., Fallon J. T., Friedlich A. L., Fisher C. M., Am. J. Cardiol. 40(4):509-13, 1977; Wolf P. A., Abbot R. D., Kannel W. B., Arch. Intern. Med. 147(9):1561-4, 1987; Wolf P. A., Abbot R. D., Kannel W. B. Stroke 22(8):983-8, 1991; Cabin H. S., Clubb K. S., Hall C., Perlmutter R. A., Feinstein A. R., Am. J. Cardiol. 65(16):1112-6, 1990).
Atrial fibrillation can be divided into three groups based on the duration of the AF episode and the refractoriness to cardioversion. The three groups are: paroxysmal, persistent and permanent, in decreasing order of receptivity to treatment. Permanent AF is resistant to any form of pharmacological treatment and cardioversion, and therefore patients with permanent AF may be considered candidates for therapies such as the MAZE procedure and can be treated with either calcium channel blockers or β-blockers to control ventricular rate.
In the remaining two categories of paroxysmal and persistent AF, treatment has a dual intent. Firstly, if a patient is in AF, physicians may wish to restore normal sinus rhythm (AF conversion). Secondly, after the patient has successfully attained normal sinus rhythm the physician will attempt to maintain normal sinus rhythm and prevent recurrence of AF.
If a patient is in AF, the physician may elect to restore sinus rhythm by the use of pharmacological rhythm control agents such as ion channel modulating compounds as described in PCT Published Patent Application No. WO 1999/50225; PCT Published Patent Application No. WO 2000/047547; PCT Published Patent Application No. WO 2004/098525; PCT Published Patent Application No. WO 2004/099137; PCT Published Patent Application No. WO 2005/018635; and U.S. Published Patent Application No. US 2005002693, or alternatively, to allow AF to continue, and ensure that ventricular rate is controlled (correcting tachycardia-induced cardiomyopathy).
The AFFIRM (Atrial Fibrillation Follow-up Investigation in Rhythm Management, 2001) trial and RACE (Rate Control Equal to Rhythm Control) trial examined comparative efficacy and mortality rates between AF patient groups using either rhythm control or rate control drugs. Results of these studies indicated that rate and rhythm control are equivalent in efficacy in relatively asymptomatic patients with atrial fibrillation. The AFFIRM trial randomized patients to medical therapy either to restore atrial rhythm or to control ventricular heart rate, whereas RACE compared medical therapy to control heart rate with electrocardioversion of rhythm. The primary study endpoint of the AFFIRM trial, total mortality, was slightly lower in the rate-control arm, although the trend was not statistically significant. Outcomes were approximately the same for the two groups in the secondary endpoint, ischemic stroke. In the RACE study, the difference between primary endpoints was also small. It was reported that patients with hypertension in particular did not do well with electrocardioversion for rhythm control. The rate of mortality, thromboembolism, or other severe complications was approximately 19 percent for rate-control therapy vs. approximately 31 percent for rhythm control.
There are two classes of antiarrhythmic agents that restore and maintain sinus rhythm through rhythm control; Class I and Class III antiarrhythmics. A summary of their ion channel blocking profiles and mechanism of action is as follows:
Class IA: Sodium channel blockers that prolong ventricular repolarization, including quinidine, procainamide, disopyramide
Class IB: Sodium channel blockers that shorten ventricular repolarization, including lidocaine, mexiletine, tocamide, phenyloin
Class IC: Sodium channel blockers with little effect on ventricular repolarization, including encamide, flecamide, propafenone
Class III: Potassium channel blockers that primarily prolong ventricular repolarization, including amiodarone, bretylium, d,i-sotalol, ibutilide, azimilide
The SWORD study (Waldo, A L et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. Lancet 1996, 348, 7-12) has shown that optically pure d-sotalol increased mortality by 65% compared to placebo. In light of those results, K. Stoschitzky et al (Stoschitzky, K. et al., Racemic beta-blockers—fixed combinations of different drugs. J. Clin. Cardiol. 1998, 1, 14-18) suggest to replace the currently used racemic mixtures with the optically pure 1-enantiomers.
There are two classes of antiarrhythmic agents that restore and maintain sinus rhythm through rate control; Class II and IV antiarrhythmics. A summary of their ion channel profiles and mechanism is as follows:
Class II: β-adrenergic blocking drugs that indirectly reduce ICa-L current in SA nodes, and AV nodes, including propranolol, atenolol, metoprolol, esmolol, timolol
Class IV: Calcium channel blockers that block ICa-L current, thus slowing conduction in SA and AV nodes and depressing contractility in all heart myocytes, including verapamil, diltiazem
The VERDICT (Verapamil versus Digoxin Cardioversion Trial, Van Noord, T. et al., VERDICT: The Verapamil versus Digoxin Cardioversion Trial: A Randomized Study on the Role of Calcium Lowering for Maintenance of Sinus Rhythm after Cardioversion of Persistent Atrial Fibrillation. J. Cardiovasc. Electrophysiol. 2001, 12, 766-769) has shown that the use of calcium-lowering drugs alone initiated pre-ECV (electrical cardioversion) and continued post-ECV seems to be insufficient to prevent subacute relapses.
AF patients are commonly treated with various agents, such as β-blockers, to control ventricular rate (Van Gelder, I. C. et al. A comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation. N. Engl. J. Med. 2002, 347 (23), 1834-1840; Basler, J. R. et al. β-Adrenergic Blockade Accelerates Conversion of Postoperative Supraventricular Tachyarrhythmias. Anesthesiology 1998, 89 (5), 1052-1059 and Yahalom, J. Beta-Adrenergic Blockade as Adjunctive Oral Therapy in Patients wuth Chronic Atrial Fibillation. Chest 1977, 71 (5), 592-596) β-adrenoceptor-blocking agents depress sinus node automaticity and inhibit atrioventricular nodal function by prolonging refractoriness and slowing conduction (Sung, R. J. et al. Beta-Adrenoceptor Blockade: Electrophysiology and Antiarrhythmic Mechanisms. Am. Heart J. 1984, 108, 1115-1120 and Kowey, P. R. et al. Electrophysiology of Beta Blockers in Supraventricular Arrhythmias. Am. J. Cardiol. 1987, 60, 32D-38D).
There remains a need in the art to identify new antiarrhythmic treatments, for both ventricular arrhythmias as well as for atrial arrhythmias. The present invention fulfills this need, and further provides other related advantages.
Related Literature
Certain ion channel modulating agents are disclosed in PCT Published Patent Application No. WO 1999/50225; PCT Published Patent Application No. WO 2000/047547; PCT Published Patent Application No. WO 2004/098525; PCT Published Patent Application No. WO 2004/099137; PCT Published Patent Application No. WO 2005/018635; and U.S. Published Patent Application No. US 2005002693.